PROJECT SUMMARY We are in the midst of a genomic revolution; more than 250,000 human genomes have been sequenced, generating over a petabase of genomic data. While these new data hold great promise to impact health, there is a disconnect between genomic discovery and clinical care. Providers frequently misinterpret genomic information, patients often don't understand their own test results, and genomic information about disease risk is infrequently shared between patients and family members. Importantly, ineffective communication and data misinterpretation has devastating consequences- including unnecessary organ removal, missed disease prevention opportunities, and premature death. We are addressing these genomic care gaps by developing and testing tools that optimize the integration of whole-exome and whole-genome sequencing (WES, WGS) for general clinical practice. My vision for improving genomic medicine is based on my work within multidisciplinary consortia and addresses the National Human Genome Research Institute's priority research area of improving the effectiveness of healthcare. In the proposed work we will test the effectiveness of a multilevel genomic e-Health intervention in cancer (Aim 1). Our intervention 1) educates physicians and patients about genomics, 2) enables direct-to-patient return-of- results, 3) provides physicians with patient-specific results and resources for interpretation, and 4) facilitates sharing of genomic results within families. We hypothesize that intervention use will result in higher rates of uptake of high-quality, genetically guided care. We will test our hypothesis in a randomized controlled trial among academic and community physicians who use WES for their patients. Next, we will use an iterative process, with stakeholder engagement, to adapt and pilot test our tool for Spanish and Mandarin speaking patients and for patients who have diabetes (Aim 2). Finally, we will create and assess new, moderated, social networks as a platform for genomic information sharing (Aim 3). Our hypothesis is that providers, patients and family members will engage with the genomic information sharing social networks and find them to be highly useful. Our general approach includes 1) creating the secure social networks, 2) integrating the networks into our e-Health intervention, and 3) using complementary methods, such as interviews and natural language processing, to assess stakeholders' network-related attitudes and network information quality. If successful, we will be well positioned to widely disseminate our e-Health tools. In sum, this work stands to transform how people obtain, process and share genomic information in the context of clinical care. Our tools reconceive genetic communication to allow for multi-directional flow of information, connects multiple stakeholders with one another, and integrates high-quality dynamic web-based resources to improve genomic care. In creating and deploying tools that both respond to and leverage the complexities of our information environment, we intend to transform genomic research and clinical practice.